This invention concerns semi-synthetic pharmaceutical chemistry, and relates to novel solvate forms of a macrolide antibiotic. More particularly, this invention provides the acetone, 1-propanol, 2-propanol, and 1-butanol solvates of the macrolide antibiotic dirithromycin. The stable solvates provide an efficient method of isolating pharmaceutically acceptable dirithromycin in excellent purity and yield.
Dirithromycin, also known as 9-deoxo-11-deoxy-9,11-{imino[2-(2-methoxyethoxy)ethylidene]oxy}-(9S,16R)-e rythromycin, is a macrolide antibiotic derived from erythromycin. The antibiotic is described in Example 9 of U.S. Pat. No. 4,048,306 of Boehringer Ingelheim. The spectrum of activity of this antibiotic approximates that of erythromycin; however, dirithromycin has the distinct advantageous property of providing high concentrations of antibiotic activity in the tissues while the plasma levels of the antibiotic remain low. To date, however, purification of this antibiotic has been difficult and somewhat inefficient.
The formation of solvates is known to be a highly individualistic effect. Dirithromycin is known to crystallize as a solvated crystal from acetonitrile; however, the acetonitrile solvate of dirithromycin is known to be unstable. See P. Lugar, R. Maier, Molecular Structure of 9-deoxy-11-deoxy-9-11-(imino(2-(2-methoxyethoxy)ethylidene)oxy)-(9S)-eryth romycin, a new erythromycin derivative, 9 Journal of Crystal and Molecular Structure 329 (1979).
Applicants have discovered that dirithromycin exists in two forms which are distinguishable by x-ray powder diffractometry. The two forms are designated Form I and Form II. Dirithromycin prepared by the method described in U.S. Pat. No. 4,048,306 is produced in the form of a polymorph which is hereinafter referred to as "Form I". Form I dirithromycin has the following x-ray powder diffraction pattern, wherein d represents the interplanar spacing and I/I.sub.o the relative intensity:
______________________________________ d(.ANG.) I/I.sub.o ______________________________________ 11.28 1.00 9.81 0.35 8.53 0.76 7.67 0.23 7.12 0.02 6.94 0.02 6.66 0.10 6.39 0.09 5.97 0.21 5.65 0.69 5.42 0.67 5.18 0.23 4.98 0.08 4.83 0.31 4.64 0.07 4.43 0.40 4.26 0.17 4.14 0.05 4.06 0.15 3.86 0.15 3.76 0.17 3.62 0.10 3.50 0.08 3.43 0.03 3.35 0.07 3.04 0.07 2.95 0.02 2.88 0.02 2.84 0.02 2.71 0.03 2.66 0.02 2.58 0.03 ______________________________________
Unfortunately, Form I is metastable and is therefore not well suited for use in pharmaceutical formulations such as tablets. However, surprisingly, and in accordance with the invention, it has now been discovered that the second polymorph of dirithromycin, hereinafter referred to as "Form II", is stable, and therefore is well adapted for use in pharmaceutical formulations such as tablets.
The new purified Form II dirithromycin had the following x-ray powder diffraction pattern, wherein d represents the interplanar spacing and I/I.sub.o the relative intensity:
______________________________________ d(.ANG.) I/I.sub.o ______________________________________ 14.17 0.02 11.96 0.27 10.43 0.11 9.65 1.00 8.86 0.84 8.18 0.54 7.07 0.33 6.99 0.10 6.84 0.21 6.59 0.03 6.24 0.05 6.07 0.29 5.97 0.19 5.77 0.06 5.54 0.36 5.50 0.47 5.45 0.26 5.13 0.22 5.11 0.29 4.84 0.29 4.75 0.47 4.72 0.42 4.50 0.62 4.44 0.31 4.24 0.20 4.20 0.05 4.11 0.17 4.09 0.18 3.92 0.14 3.87 0.12 3.83 0.12 3.73 0.06 3.55 0.08 3.49 0.15 3.46 0.07 3.42 0.11 3.33 0.05 3.17 0.04 3.11 0.02 2.96 0.04 2.83 0.02 2.74 0.04 2.57 0.03 ______________________________________
The Form I crystal can be isolated via the acetonitrile solvate of dirithromycin and exposure of the solvate to air or vacuum drying. The method of preparing Form I dirithromycin is described in U.S. Pat. No. 4,048,306 of Boehringer Ingelheim, which is hereby incorporated by reference.
The disadvantage of Form I is that it is metastable, i.e. it gradually converts to a mixture containing the second crystal type, Form II, with time. This conversion is accelerated with increased temperature. The conversion of crystalline Form I to Form II occurs at temperatures from about 80.degree. C. to about 130.degree. C.
It is desirable to isolate the pure Form II crystal of dirithromycin to assure uniformity of product. The method of this invention provides isolated Form II dirithromycin of greatly improved quality via a convenient, efficient, and ecologically friendly isolation process.